Opioid activity of enkephalin analogues containing the kyotorphin-related structure in the N-terminus.

The pharmacological activity of eight analogues of enkephalin containing L-Arg or D-Arg in position 2 were examined. All peptides showed weaker inhibitory effects than those of naturally-occurring enkephalins on the isolated guinea-pig ileal longitudinal muscle and the mouse vas deferens. On the contrary, these eight peptides were more potent than enkephalins in the analgesic test involving intracisternal administration to mice. By the intravenous route, only D- Arg2 -Met5-enkephalin, which induced a most potent analgesia by intracisternal injection, was effective. D- Arg2 -Met5-enkephalin showed a similar binding affinity to that of Met5-enkephalin in the opioid mu-receptor binding assay, but had a lower delta-receptor binding affinity than did Leu5-enkephalin. Administration of thiorphan , an enkephalin dipeptidyl carboxypeptidase inhibitor, did not potentiate the analgesic effect of D- Arg2 -Met5-enkephalin, whereas it dramatically enhanced the effect of D-Ala2-Met5-enkephalin, when both drugs were administered concomitantly into the cisterna magna of mice.